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Abstract

Background Autologous implantation of peripheral blood mononuclear cells (PB-MNCs) has been shown to induce angiogenesis through supplying endothelial progenitor cells (EPCs) and multiple angiogenic factors. Although granulocyte colony-stimulating factor (G-CSF) is used to enhance EPC mobilization, it may cause serious complications in patients with cardiovascular diseases. Recombinant human erythropoietin (rhEPO) has been shown to enhance mobilization of EPCs to circulating blood. We hypothesized that rhEPO administration with phlebotomy for autologous blood donation might enhance the number of functionally active circulating progenitor cells in peripheral blood, resulting in a novel strategy for therapeutic angiogenesis.

Methods and Results Levels of circulating CD34+ and CD34+/CD133+ MNCs were measured by flow cytometry in 20 patients who underwent blood donation (400 ml) alone or with single rhEPO administration (24000 IU) for hip surgery. The numbers of CD34+ and CD34+/CD133+ MNCs were significantly increased one week after blood donation (CD34+ MNCs: from 943 ± 99 to 1272 ± 141/ml, P < 0.01; CD34+/CD133+ MNCs: from 615 ± 69 to 842 ± 98/ml, P < 0.01). The combination of blood donation and rhEPO administration resulted in a significantly greater increase in the number of CD34+ and CD34+/CD133+ MNCs than that in the case of blood donation alone. Multivariate analysis showed that administration of rhEPO was a significant independent factor for the maginitude of increase in CD34+/CD133+ MNCs. PB-MNCs, which were collected by apheresis after blood donation and rhEPO administration, were implanted in five patients with critical limb ischemia with no therapeutic option. Despite the smaller number of implanted PB-MNCs (1.1 ± 0.2 × 1010 cells) compared with the numbers in previous studies using G-CSF, the ischemic status evaluated by rest-pain scale and photoplethysmography was improved without any serious complication in three of the five patients. Non-healing ulcers in one patient disappeared after the treatment.

Conclusions Administration of rhEPO with autolougous blood donation may be a novel and secure strategy to enhance mobilization of functionally active circulating progenitor cells for vascular regeneration.